1999 Pharmacy Handbook - Medicinal chemistry II

Medicinal chemistry II

Introduction
General objectives
Syllabus
Practical
Textbooks
Assessment

Introduction

Dr Ted Lloyd
68 lectures, 13 tutorials and 66 hours of practical work.
The aim of the subject is to build on the basic physical and organic chemistry taught in 'Medicinal chemistry I', and to apply it to aspects of chemistry relevant to pharmacy.
The lecture course will be presented in two semester units. Students will be advised of the topics in each unit at the beginning of the first semester.

General objectives

In this teaching program students are expected to develop:

understanding of the nomenclature and meaning of terms used to describe the three-dimensional structures (stereochemistry) of drug molecules; spectroscopic methods used in the analysis and structural determination of drugs; the theory and application of thermodynamics; the structural and mechanistic bases for the action of the autonomic neurotransmitters and related agents; factors affecting the physicochemical properties and reactivity of drugs based on aromatic frameworks; factors influencing the three-dimensional structures of proteins; the partition of substances between various phases as applied to both the analysis of drugs and their transport in the body; principles of electrochemistry applied in the analysis of drugs; the chemical principles underlying selected diagnostic aids relevant to pharmacy; the application of radioisotopes in pharmacy;
abilities in the areas of the measurement and recording of data relevant to the understanding of drug structure and reactivity; numerical calculations based on experimental or theoretical data; report writing or oral presentations based on the results of experimental work;
an appreciation of the general chemical principles of enzymatic catalysis; the importance of chemical reactions in determining drug transport and metabolism; the application of the principles of medicinal chemistry to the search for selectivity in therapeutic agents.

Syllabus

Autonomic nervous system agents. Cholinergic system: muscarinic and nicotinic receptors; structure and activity of acetylcholine and acetylcholinesterase; reversible and irreversible inhibition of acetylcholinesterase; treatment of anticholinesterase poisoning; cholinergic blocking agents and their use as muscle relaxants; degradation of muscle relaxants. Adrenergic system: structure and function of noradrenaline; inactivation of noradrenaline by monoamine oxidase and catecholamine-O-methyl transferase; [alpha]- and [beta]-adrenoceptors; chemistry of [alpha]-adrenergic antagonists; chemistry and selectivity of [beta]-active agents.
Structural determination and analysis of drugs. Molecular geometry, symmetry, isomerism, configuration, conformation, conformational analysis; the use of conformationally restricted analogues in determining receptor structure and the shape of active drugs; preparation of homochiral compounds, implications of stereo-chemistry for drug design and delivery. NMR, IR, UV spectroscopy, mass spectrometry - underlying processes and applications in the pharmaceutical industry; interpretation of spectra; identification of compounds using spectroscopic techniques.
Reactivity and molecular interactions of drugs. Differences between aromatic and aliphatic compounds; resonance theory and stabilisation, acid/base properties; linear free-energy relationships, Hammett plots, sigma and rho values, effect of substituents on drug stability; steric effects; structure-activity relationships in local anaesthetics; heterocyclic aromatic compounds - nomenclature and properties, role of heterocyclic compounds in biological systems. Catalysis of reactions, particularly ester and amide hydrolysis; pH rate profiles; transition-state stabilisation, general acid and general base catalysis, nucleophilic catalysis, metal-ion catalysis, and their role in reactions catalysed by enzymes; pyridoxal phosphate dependent enzymes; enzymes as targets for drugs.
Energy changes in biological processes. Reversible, irreversible and spontaneous processes; disorder, entropy, free energy; equilibrium constants; entropy and enthalpy-driven processes; coupled reactions; measurement of [Delta]G; calculation of free-energy changes, van't Hoff plots; applications of thermodynamic concepts to biochemical reactions, conformational equilibria, phase transitions, and drug-receptor interactions.
Biologically important macromolecules and their interactions. Chemistry of the peptide bond; factors affecting primary, secondary and tertiary structure of proteins; functional groups involved in binding of drugs to protein; thermodynamics of drug binding, stereochemistry, drug binding and the three-dimensional structure of proteins; techniques involved in determining protein structure. Structure and properties of biologically relevent carbohydrates.
Clinical chemistry. Types and units of radiation, maximum doses, background radiation; protection required for different forms of radiation; technetium generators and production of isotopes of pharmaceutical interest; preparation of radiopharmaceutical dose forms; X-ray and radio-isotopic imaging; the use of isotopes in sterilisation. Activity, ionic strength, junction potentials; Debye-Huckel theory, Ferguson principle for drug equi-action; ion-selective electrodes, pH measurements, amperometric electrodes, and their role in pharmacy/clinical chemistry; composition of pharmaceutical glasses; biological cell potentials. Sampling techniques, clinical stick devices, tests for nitrate, pH, glucose, protein and cholesterol, and their clinical significance; tests for enzymes and lipoproteins; drug interferences in clinical tests. Liquid-liquid distribution, extraction efficiency; principles underlying HPLC, gas, gas-liquid, partition and thin-layer chromatography; relationship between pH, drug structure, dissolution medium and drug distribution, electrophoresis.

Practical

66 hours of practical work.
Practical classes are designed to reinforce chemical principles taught in the lecture series and to illustrate the analytical bases of quality assurance for pharmaceutical products. Emphasis is placed on technique and general methods. Performance in laboratory classes is taken into account in assessing students' results in this subject.

Textbooks

Recommended texts

As prescribed for 'Medicinal chemistry I' and
Solomons T W G Organic chemistry 6th edn, Wiley, 1996
Victorian College of Pharmacy Medicinal chemistry II laboratory manual VCP, 1999

Reference books

As prescribed for 'Medicinal chemistry I' and
Branden C and Tooze J Introduction to protein structure Garland, 1991
Chang R Physical chemistry with applications to biological systems 2nd edn, Macmillan, 1981
Delgado J N and Remers W A Wilson and Gisvold's 'Textbook of organic medicinal and pharmaceutical chemistry' 9th edn, Lippincott, 1991
Fersht A R Enzyme structure and mechanism 2nd edn, Freeman, 1985
Field L D Organic structures from spectra 2nd edn, Wiley, 1995
Florence A T and Attwood D Physicochemical principles of pharmacy 3rd edn, Macmillan, 1998
Foye W O Principles of medicinal chemistry 4th edn, Lea and Febiger, 1995
Griffiths P J F and Thomas J D R Calculations in advanced physical chemistry 3rd edn, Arnold, 1983
Kaplan L A and Pesce A J Clinical chemistry 3rd edn, Mosby, 1996
Kemp W NMR in chemistry, a multinuclear introduction MacMillan, 1986
Martin A N and others Physical pharmacy 4th edn, Lea and Febiger, 1993
Moran L A and others Biochemistry 2nd edn, N Patterson, 1994
Selinger B Chemistry in the marketplace 5th edn, Harcourt, 1998
Silverman R B The organic chemistry of drug design and drug action Academic, 1992
Silverstein R M and others Spectrometric identification of organic compounds 6th edn, Wiley, 1998
Sykes P A guidebook to mechanism in organic chemistry 6th edn, Longman, 1986
Vogel A I Vogel's 'Textbook of practical organic chemistry' 5th edn, Longman, 1989
Vogel A I Vogel's 'Textbook of quantitative chemical analysis' 5th edn, Longman, 1989

Assessment

Subject assessment will reflect the learning objectives outlined above. Methods of assessment will include:

Mid-year examination (June) (First semester) (3 hours): 45%
Practical work: 10%
End-of-year examination (Second semester) (3 hours): 45%